1. Field of the Invention
This invention relates to characterization of the effects of IL-17F binding to IL-17R; in particular, the invention relates to the effects of IL-17F binding to IL-17R on airway inflammation, e.g., in patients with cystic fibrosis, including pulmonary exacerbations due to bacterial infections in same.
2. Related Background Art
IL-17A is a proinflammatory cytokine that regulates both granulopoiesis and recruitment of neutrophils into sites of inflammation (Yao et al. (1995) J. Immunol. 155:5483-86; Ye et al. (2001) J. Exp. Med. 194:519-28; Kolls et al. (2003) Am. J. Respir. Cell Mol. Biol. 28:9-11; Laan et al. (1999) J. Immunol. 162:2347-52; Linden et al. (2000) Eur. Respir. J. 15:973-77). This is due, in part, to the ability of IL-17A to both induce the release of CXC chemokines and regulate the expression of G-CSF, a critical granulopoietic growth factor (Laan, supra; Moseley et al. (2003) Cytokine Growth Factor Rev. 14:155-74; Jones and Chan (2002) Am. J. Respir. Cell Mol. Biol. 26:748-53; Ye et al. (2001) Am. J. Respir. Cell Mol. Biol. 25:335-40; Ye et al. (2001) J. Exp. Med. 194:519-28). Mice with a homozygous deletion of the receptor to IL-17A, i.e., IL-17 receptor (IL-17R), have enhanced lethality, defective neutrophil recruitment, and decreased granulopoiesis to experimental Gram-negative pneumonia (Ye et al. (2001) J. Exp. Med. 194:519-28). However, they do not have an increased susceptibility to intracellular infections caused by Listeria monocytogenes or Mycobacteria tuberculosis (unpublished observations). This defect in host defense is likely due, in part, to a greater than 90% reduction in G-CSF in response to Gram-negative bacterial challenge in IL-17R-deficient mice compared to control mice, as well as a significantly attenuated response to infection (Ye et al. (2001) J. Exp. Med. 194:519-28).
Recently five other proteins, in addition to IL-17A, have been identified as members of the IL-17 family of proteins; IL-17F has the closest sequence homology (58% at the protein level) to IL-17A, as well as similar induction of CXC chemokines and similar neutrophil-mobilization profiles (Moseley et al., supra; Li et al. (2000) Proc. Natl. Acad. Sci. USA 97:773-78; Starnes et al. (2001) J. Immunol. 167:4137-40; Starnes et al. (2002) J. Immunol. 169:642-46; Hurst et al. (2002) J. Immunol. 169:443-53; Aggarwal and Gurney (2002) J. Leukoc. Biol. 71:1-8; Hymowitz et al. (2001) EMBO J 20:5332-41). IL-17A and IL-17F lie immediately adjacent to each other on mouse chromosome 1 and human chromosome 6, and both cytokines are produced by T cells in response to IL-23 (Chmiel et al. (2002) Clin. Rev. Allergy Immunol. 23:5-27; Aggarwal et al. (2003) J. Biol. Chem. 278(3):1910-14; Happel et al. (2003) J. Immunol. 170:4432-36; Kolls et al. (2004) Immunity 21:467-76). Furthermore, IL-17A and IL-17F are induced in a similar time course in the lung in experimental Gram-negative pneumonia (unpublished observations). Although IL-17F has a lower affinity for IL-17R, by an order of magnitude as compared to IL-17A, there has been some speculation as to whether both IL-17A and IL-17F signal via IL-17R because the two proteins share similar biological activities (Hymowitz et al., supra).
To date, the interaction between IL-17F and IL-17R has not been characterized. Consequently, a direct correlation between IL-17F-mediated signaling and airway inflammation has not been proven definitively. The present invention provides this correlation. In particular, the correlation provided by the present invention allows for the diagnosis, prognosis, monitoring and/or treating of airway inflammation, e.g., in patients with cystic fibrosis, including pulmonary exacerbations due to bacterial infections in same, via methods that detect IL-17F.